Ibutamoren compressed oral formulation

Abstract

The present disclosure relates to pharmaceutical solids and compositions comprising ibutamoren or a pharmaceutically acceptable salt thereof, and methods of administration to pediatric subjects for the treatment of growth hormone deficiency.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 422,329, filed on November 3, 2022, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Growth hormone deficiency (GHD) leading to pediatric short stature (height of -2 standard deviations (SD) of chronological age) is a disease seen worldwide. The current treatment for short children with GHD usually continues for many years from childhood diagnosis until final height is reached. Typically, more than one year of treatment is required to establish a new growth trajectory with treatment. Thereafter, it is often necessary for these children to receive treatment for more than ten years until they reach optimal adult height. Furthermore, the results obtained from a six - month treatment evaluation in newly diagnosed children can vary greatly due to the underlying cause of GH deficiency and differences in the catch - up growth pattern and rate at the start of treatment. Children with GHD are usually treated with daily subcutaneous injections of GH, which is painful, inconvenient, and there are children, especially young children, who feel pain.

[0003] Therefore, developing a non - injection - dependent treatment method, such as once - daily oral treatment, that is effective for the treatment of pediatric GHD would be beneficial in terms of treatment ease, patient convenience, and long - term medication compliance.

[0004] This disclosure addresses these and other unmet needs.

Summary of the Invention

[0005] In some aspects, the disclosure provides a pharmaceutical solid comprising ibutamoren or a pharmaceutically acceptable salt thereof, wherein ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount greater than 10% by weight of the pharmaceutical solid, and the weight of the pharmaceutical solid is less than about 20 mg.

[0006] In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is ibutamorene mesylate.

[0007] In some embodiments, the pharmaceutical solid is a tablet, a minitablet, a sprinkle, or a bead.

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a plurality of pharmaceutical solids disclosed herein.

[0009] In some embodiments, the composition is in the form of a capsule containing 1 to 12 tablets as disclosed herein. In some embodiments, the tablets are minitablets. In some embodiments, the tablets are minitablets having a diameter of less than 3 mm.

[0010] In some embodiments, the present disclosure provides a method for treating growth hormone deficiency, the method comprising administering one or more pharmaceutical forms or pharmaceutical compositions disclosed herein to a subject in need thereof.

[0011] In some embodiments, the subjects are human children aged 2 to 20 years. [Brief explanation of the drawing]

[0012] [Figure 1] A flowchart outlining the process for manufacturing the drug tablets of this disclosure containing ibutamoren mesylate is shown. [Modes for carrying out the invention]

[0013] definition Unless otherwise specified, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of the field of this disclosure. The following references provide general definitions of many of the terms used herein to those skilled in the art: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). Where used herein, the following terms have the meanings given below unless otherwise specified.

[0014] As used herein, the verb “comprise” and its variations as used in this description and in the claims are used in their non-restrictive sense, meaning that the items following the word are included, but not excluded, items not specifically mentioned. This disclosure may preferably “comprise,” “consist of,” or “consist essentially of” the steps, elements, and / or reagents described in the claims.

[0015] Unless specifically stated or evident from the context, the term "or" is understood to be inclusive when used herein. Unless specifically stated or evident from the context, the terms "a," "an," and "the" are understood to be singular or plural when used herein.

[0016] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numbers and / or ranges. The term “about” is understood to mean values ​​that are close to the values ​​listed. Furthermore, the phrases “less than approximately [value]” or “greater than approximately [value]” should be understood in light of the definition of the term “about” provided herein. The terms “about” and “approximately” may be used interchangeably.

[0017] As used herein, "D90" refers to the 90th percentile value of the particle size determined by sieving analysis, i.e., the percentage of drug particles retained on the mesh screen during the sieving process using a screen of a specific mesh size. For example, if D90 = 100 μm, 90% of the drug particles remain on the 100 μm mesh screen during the sieving process. Similarly, "D80" refers to the 80th percentile value of the particle size, "D70" to the 70th percentile value, "D60" to the 60th percentile value, "D50" to the 50th percentile value, "D40" to the 40th percentile value, "D30" to the 30th percentile value, "D20" to the 20th percentile value, and "D10" to the 10th percentile value.

[0018] As used herein, “substantially” or “substantial” refers to the complete or near-complete range or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is “substantially” sealed means that the object is either completely sealed or nearly completely sealed. The strict tolerance for deviation from absolute completeness may, in some cases, depend on the specific context. However, generally speaking, proximity to completeness means that the same overall result is obtained as if absolute and complete completeness had been achieved. The use of “substantially” is equally applicable when used in a negative implication referring to the complete or near-complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition that is “substantially” free of other activators either completely lacks the other activators or nearly completely lacks them to the extent that the effect is the same as if the other activators were completely lacking. In other words, a composition that is “substantially” free of a component or element or other activator may contain such a substance, as long as there is no measurable effect.

[0019] The term “treatment” means one or more of the following: relief, reduction, delay, decrease, recovery, improvement, or management of at least one symptom of the condition in question. The term “treatment” may also mean one or more of the following: halting the progression of symptoms, delaying the onset of symptoms (i.e., the period before symptoms become clinically apparent), or reducing the risk of developing or worsening symptoms.

[0020] The term "therapeutically effective" as applied to dosage or quantity refers to the amount of compound or pharmaceutical formulation that, after administration to the target (e.g., a human child), produces the desired clinical benefit.

[0021] As used herein, "prepubertal" refers to a child with a bone age of < 8 years in girls and < 9 years in boys. The bone age can be determined using well-known methods such as the Greulich and Pyle atlas matching method or the Tanner and Whitehouse scoring system. Other examples of bone age include < 7 years in females and < 8 years in males.

[0022] As used herein, "preadolescent" refers to a child who has begun to experience puberty, clinically evaluated by the Tanner staging classification. Tanner stage 1 is prepubertal, and any stage up to the end of puberty (Tanner stage 4) is considered preadolescent.

[0023] As used herein, "short stature" refers to a child having a height less than the 2.3 percentile (height at approximately -2SD of chronological age) for the child's chronological age. Other examples include less than the 5 percentile, 4 percentile, 3 percentile, 2 percentile, and 1 percentile for the child's chronological age.

[0024] As used herein, "growth delay" or "decrease in growth rate of height" refers to a growth rate of height recorded over at least 6 months being less than the 25 percentile for age and gender. Other examples include, for a record of at least 6 months, less than the 24 percentile, 23 percentile, 22 percentile, 21 percentile, 20 percentile, 19 percentile, 18 percentile, 17 percentile, 16 percentile, 15 percentile, 14 percentile, 13 percentile, 12 percentile, 11 percentile, 10 percentile, 9 percentile, 8 percentile, 7 percentile, 6 percentile, 5 percentile, 4 percentile, 3 percentile, 2 percentile, and 1 percentile for age and gender.

[0025] As used herein, "sufficient GH secretory capacity" refers to a patient who is considered to have sufficient GH secretory capacity when the subject meets the following conditions. o(i) having a peak GH concentration of < 10 μg / L (or < 7 μg / L) in response to a standard stimulation test, o(ii) having a peak serum GH of ≧ 5 μg / L in response to a single administration of ibutamoren mesylate (e.g., 0.8 mg / kg).

[0026] As used herein, "equivalent growth potential compared to rhGH" refers to a patient who is considered to have equivalent growth potential (equivalent growth potential compared to rhGH) compared to chronic subcutaneous injection of rhGH when the subject meets the following conditions. o(i) having a peak serum GH of ≧ 5 μg / L in response to a single administration of ibutamoren mesylate (e.g., 0.8 mg / kg), o(ii) having a baseline serum IGF-I of > 30 μg / L.

[0027] All weight percentages referred to herein (i.e., "weight %", "wt.%", and "w / w") are measured with respect to the total weight of the solid pharmaceutical form or pharmaceutical composition, unless otherwise indicated.

[0028] Pharmaceutical solid In some embodiments, the present disclosure provides a pharmaceutical solid comprising ibutamoren or a pharmaceutically acceptable salt thereof, wherein ibutamoren or a pharmaceutically acceptable salt thereof is present in an amount greater than 10% by weight of the pharmaceutical solid, and the weight of the pharmaceutical solid is less than about 20 mg.

[0029] Ibutamoren is a non-peptide agonist of ghrelin and a growth hormone secretagogue having the following structure,

Chemical formula

[0030] Ibutamoren mesylate, N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperzine]-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate, is known as MK-0677 and LUM-201 and has been evaluated in multiple clinical trials.

[0031] In some embodiments, the pharmaceutical solids of the present disclosure contain ibutamorene or a pharmaceutically acceptable salt thereof in amounts exceeding 10% by weight, exceeding 12.5% ​​by weight, exceeding 15% by weight, exceeding 17.5% by weight, exceeding 20% ​​by weight, exceeding 22.5% by weight, exceeding 25% by weight, exceeding 27.5% by weight, exceeding 30% by weight, exceeding 32.5% by weight, exceeding 35% by weight, exceeding 37.5% by weight, exceeding 40% by weight, exceeding 42.5% by weight, and exceeding 45% by weight. It is contained in amounts greater than, greater than 47.5% by weight, greater than 50% by weight, greater than 52.5% by weight, greater than 55% by weight, greater than 57.5% by weight, greater than 60% by weight, greater than 62.5% by weight, greater than 65% by weight, greater than 67.5% by weight, greater than 70% by weight, greater than 72.5% by weight, greater than 75% by weight, greater than 77.5% by weight, greater than 80% by weight, greater than 82.5% by weight, greater than 85% by weight, greater than 87.5% by weight, greater than 90% by weight, greater than 92.5% by weight, or greater than 95% by weight. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 10% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 20% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 30% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 40% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 50% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 60% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 70% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 80% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 85% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 90% by weight or more of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 10% by weight to about 90% by weight of the pharmaceutical solid.In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 15% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 20% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 25% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 30% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 35% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 40% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 45% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 50% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 55% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 60% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 65% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 70% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 75% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 80% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 85% to about 90% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 50% to about 80% by weight of the pharmaceutical solid.In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 55% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 60% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 65% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 70% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 75% to about 80% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 30% to about 50% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 35% to about 50% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 40% to about 50% by weight of the pharmaceutical solid. In some embodiments, ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of about 45% to about 50% by weight of the pharmaceutical solid. In some embodiments, the pharmaceutically acceptable salt is a mesylate of ibutamorene.

[0032] In some embodiments, the weight of the pharmaceutical solids of the Disclosure is less than about 20 mg, less than about 19 mg, less than about 18 mg, less than about 17 mg, less than about 16 mg, less than about 15 mg, less than about 14 mg, less than about 13 mg, less than about 12 mg, less than about 11 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than 4 mg, less than 3 mg, or less than 2 mg. In other embodiments, the weight of the pharmaceutical solids of the Disclosure is in the range of about 1.0 mg to about 20 mg, or in the range of about 2 mg to about 17 mg. In some embodiments, the weight of the pharmaceutical solids of the Disclosure is less than about 19 mg. In some embodiments, the weight of the pharmaceutical solids of the Disclosure is less than about 18 mg. In some embodiments, the pharmaceutical solids of this disclosure have a weight of about 5 mg to about 20 mg, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some embodiments, the pharmaceutical solids are tablets with a weight of about 12 mg to about 20 mg. In some embodiments, the pharmaceutical solids are tablets with a weight of about 12 mg to about 18 mg.

[0033] In another embodiment, each solid, tablet, minitablet, etc., contains a different dose of ibutamorene or a pharmaceutically acceptable salt thereof. In a particular embodiment, ibutamorene is ibutamorene mesylate.

[0034] In certain embodiments, the tablets or minitablets contain ibutamorene mesylate in amounts ranging from approximately 1 to approximately 20 mg, for example, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, or 22 mg, encompassing all values ​​and partial ranges between them. In some embodiments, the tablets or minitablets contain about 4 to about 15 mg of ibutamorene mesylate, for example, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, or 15.5 mg, including all values ​​and partial ranges between them. In some embodiments, the tablets or minitablets having a 50% by weight drug load contain about 4.7 mg of ibutamorene mesylate. In some embodiments, the tablets or minitablets having a 70% by weight drug load contain about 7.11 mg of ibutamorene mesylate. In some embodiments, a tablet or minitablet having an 85% by weight drug load contains approximately 10.36 mg of ibutamorene mesylate.

[0035] The pharmaceutical solids of this disclosure can be any suitable form known in the art. In some embodiments, the pharmaceutical solids can be designed into a desired shape, such as tablets, sprinkles, or beads. In some embodiments, the pharmaceutical solids are tablets. In some embodiments, the tablets are minitablets. In some embodiments, the tablets or minitablets are not prepared by wet granulation. In some embodiments, the solids or minitablets are prepared by roller compression of drug particles. In some embodiments, the pharmaceutical solids are one or more beads. In some embodiments, the pharmaceutical solids can be administered orally by mixing them with soft foods such as applesauce, pudding, or yogurt.

[0036] In certain embodiments, a solid is prepared after roller compression and compressed into mini-tablet form. The mini-tablet form is then further incorporated into additional dosage forms such as capsules, or administered directly to the subject as one or more mini-tablets, depending on the required drug dose for the subject.

[0037] In some embodiments, the pharmaceutical solid is a tablet with a diameter of about 5 mm or less, for example, about 4.5 mm or less, about 4 mm or less, about 3.5 mm or less, about 3.0 mm or less, about 2.5 mm or less, or about 2 mm. In some embodiments, tablets have diameters ranging from about 1 mm to about 5 mm, for example, about 1 mm, about 1.5 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, about 3.0 mm, about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about 4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, and about 4.9 mm, including all values ​​and partial ranges in between. In some embodiments, tablets have a diameter of less than about 3 mm and are called mini tablets. In some embodiments, the tablets have a diameter of less than about 2.5 mm and are called mini-tablets. In some embodiments, the mini-tablets have a diameter in the range of about 2 mm to about 3 mm. In some embodiments, the mini-tablets have a diameter of 2 mm. In some embodiments, the mini-tablets have a diameter of 2.5 mm. In some embodiments, the mini-tablets have a diameter of 2 mm. The tablets and mini-tablets disclosed herein can have any shape convenient to those skilled in the art, such as spherical, circular, elliptical, or triangular. In some embodiments, the tablets are circular. In some embodiments, the tablets are circular and convex. In some embodiments, the tablets are circular and concave.

[0038] In some embodiments, the tablets disclosed herein are compressible tablets that can be compressed by a tablet press (rotary or single-shot) or other techniques known in the art. In some embodiments, the tablets comprise drug-containing granules disclosed herein. In some embodiments, the compressible tablets comprise drug-containing granules and one or more extragranular pharmaceutical excipients. In some embodiments, the compressible tablets comprise drug-containing granules and an extragranular binder, disintegrant, and lubricant. In some embodiments, the compressible tablets comprise drug-containing granules and an extragranular disintegrant, lubricant, and optional binder. In some embodiments, the tablets are compressed with drug-containing granules disclosed herein that have been processed by roller compression, and an extragranular binder, disintegrant, and / or lubricant.

[0039] In some embodiments, one or more non-granular pharmaceutical excipients include a binder, a disintegrant, and a lubricant. In some embodiments, the amount of binder is in the range of about 1% w / w to about 5% w / w relative to the weight of the tablet, the amount of disintegrant is in the range of about 1% w / w to about 5% w / w, and the amount of lubricant is in the range of about 0.5% w / w to about 2% w / w. In some embodiments, the amount of binder is in the range of about 2% w / w to about 4% w / w relative to the weight of the tablet, the amount of disintegrant is in the range of about 2.5% w / w to about 3.5% w / w, and the amount of lubricant is in the range of about 0.25% w / w to about 1.0% w / w.

[0040] Suitable binders for non-granular materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums (e.g., sodium acacia alginate, polyvinylpyrrolidone), cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, etc.), and bee gum, as well as combinations thereof. Examples of polyvinylpyrrolidone include povidone, copovidone, and crospovidone. In some embodiments, the binder is pregelatinized starch.

[0041] Suitable disintegrants for non-granular materials include, but are not limited to, starch, clay, cellulose, algin, gum, or cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include lactose, white sugar, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. In some embodiments, one or more disintegrants are lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modified starch, croscarmellose sodium, crospovidone, sodium glycolate starch, or combinations and mixtures thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0042] Lubricants suitable for non-granular materials include, but are not limited to, magnesium stearate, calcium stearate, talc, and colloidal silica. In some embodiments, the lubricant includes stearic acid and / or stearate, such as magnesium stearate. In some embodiments, the lubricant is magnesium stearate.

[0043] In some embodiments, the binder is pregelatinized starch, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0044] In some embodiments, the Disclosure provides pharmaceutical tablets (e.g., compressed pharmaceutical tablets or compressed pharmaceutical minitablets) comprising drug-containing granules comprising about 10% to about 90% by weight of ibutamorene mesylate, about 2% to about 50% by weight of a binder, about 1% to about 35% by weight of a bulking agent, about 0.5% to about 5% by weight of a disintegrant, and about 0.1% to about 1% by weight of a lubricant, wherein the tablets, when compressed using a tablet press with a tool of less than 3 mm, have a degree of abrasion of less than 1% and a hardness greater than about 0.7 Kp.

[0045] In some embodiments, the binder is pregelatinized starch, the bulking agent is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0046] In some embodiments, the present disclosure provides tablets having compositions with drug loads (DL) ranging from 10% to 90% according to the following table.

[0047] [Table 1]

[0048] Tablets need to possess sufficient hardness and low abrasion to ensure their strength and structural integrity during packaging, transport, and end use. However, when compressing small tablets and mini-tablets (e.g., tablets with a diameter of less than 5 mm), maintaining adequate hardness and abrasion can be difficult, especially when the drug-containing granules being compressed contain high drug load levels (e.g., ibutamorene mesylate ≥ 50 wt%). As described herein, roller-compressed drug-containing granule blends unexpectedly proved to increase the proportion of large granules (e.g., granules held by 40, 60, and 80 mesh sieves), increase the density of the blend, and improve fluidity, even when drug load levels exceed 50 wt%, compared to uncompressed granules. These surprising and unexpected properties led to roller-compressed drug-containing granule blends that provide sufficient hardness and low abrasion when compressed into small tablets and mini-tablets containing approximately 10 wt% to approximately 90 wt% ibutamorene mesylate.

[0049] The ability to prepare small tablets and mini-tablets is important for improving medication adherence and providing flexible dosing plans in the treatment of children aged 2 to 20 years, as disclosed herein.

[0050] In some embodiments, the tablets disclosed herein have a hardness greater than 0.7 Kp when compressed with a compressive force of 25 kN or less, 20 kN or less, 15 kN or less, or 10 kN or less. In some embodiments, the tablets have a hardness greater than 1.5 Kp when compressed with a compressive force of 25 kN or less, 20 kN or less, 15 kN or less, or 10 kN or less. In some embodiments, the tablets have a hardness greater than 3.0 Kp when compressed with a compressive force of 25 kN or less, 20 kN or less, 15 kN or less, or 10 kN or less. In some embodiments, the tablets have a hardness of about 0.5kP to about 6kP, for example, about 0.5kP, about 1kP, about 1.5kP, about 2kP, about 2.5kP, about 3kP, about 3.5kP, about 4kP, about 4.5kP, about 5kP, about 5.5kP, or about 6kP, including all values ​​and partial ranges in between. In some embodiments, the drug load in the tablet is about 70% to about 90% by weight of the tablet, and the tablet has a hardness of about 3.2kP to about 5.5kP when prepared in a 2.5mm tablet press. In some embodiments, the drug load in the tablet is about 90% by weight of the tablet, and the tablet has a hardness of about 4.5kP to about 5.5kP when prepared in a 2.5mm tablet press. In some embodiments, the drug load in the tablet is about 70% by weight of the tablet, and the tablet has a hardness of about 3.2 kP to about 4.2 kP when prepared in a 2.5 mm tablet press. In some embodiments, the drug load in the tablet is about 50% by weight of the tablet, and the tablet has a hardness of about 1.5 kP to about 2.5 kP when prepared in a 2.5 mm tablet press. In some embodiments, the drug load in the tablet is about 30% by weight of the tablet, and the tablet has a hardness of about 1.0 kP to about 2.0 kP when prepared in a 2.5 mm tablet press. In some embodiments, the compressive force is 20 kN, 19 kN, 18 kN, 17 kN, 16 kN, 15 kN, 14 kN, 13 kN, 12 kN, 11 kN, or 10 kN or less, including all values ​​and partial ranges in between. In some embodiments, compression is performed using a tablet press.

[0051] In some embodiments, the tablets disclosed herein have a degree of abrasion of less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.3%, or less than about 0.20%. In some embodiments, the tablets have a degree of abrasion of less than about 1%. In some embodiments, the tablets have a degree of abrasion of less than about 0.75%. In some embodiments, the tablets have a degree of abrasion of less than about 0.5%. In some embodiments, the tablets have a degree of abrasion of less than about 0.3%.

[0052] The pharmaceutical tablets (e.g., minitablets) of this disclosure may be uncoated or coated with one or more coating layers. In some embodiments, the coating comprises Eudragit® E PO, Eudragit® E 100, Eudragit® E 12,5, or Opadry® amb II. In some embodiments, the coating comprises an Opadry® amb II film coating, which is a polyvinyl alcohol (PVA)-based coating that does not contain polyethylene glycol (PEG). In some embodiments, the coating comprises Eudragit® E PO, which is a functional copolymer comprising N,N-dimethylaminoethyl methacrylate, methacrylate, and butyl methacrylate monomer. In some embodiments, the coating applied to the tablet or minitablet comprises an aminoalkyl methacrylate copolymer. In some embodiments, the coating is a taste masking layer. In some embodiments, the coating is applied to the tablet with a weight increase of about 1% to about 30%, based on the total weight of the pharmaceutical solid (dry polymer weight), for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, encompassing all values ​​and partial ranges between them. In some embodiments, the coating is applied to the tablet to result in a weight increase of about 5% to about 25%, based on the total weight of the pharmaceutical solid. In some embodiments, the coating is applied to the tablets with a weight increase of about 8% to about 20%, for example, about 8%, about 10%, about 12%, about 16%, or about 20%, based on the total weight of the pharmaceutical solid, including all values ​​and partial ranges in between. In some embodiments, the coating is applied to the tablets to result in a weight increase of about 8%, based on the total weight of the pharmaceutical solid. In some embodiments, the coating is applied to the tablets to result in a weight increase of about 10%, based on the total weight of the pharmaceutical solid.In some embodiments, the coating is applied to the tablets to increase their weight by about 12% based on the total weight of the pharmaceutical solids. In some embodiments, the coating is applied to the tablets to increase their weight by about 16% based on the total weight of the pharmaceutical solids. In some embodiments, the coating is applied to the tablets to increase their weight by about 20% based on the total weight of the pharmaceutical solids. The coating may be applied by any method known in the art, including spraying a polymer or a plurality of polymers onto the tablets or minitablets described above. In some embodiments, the coating is applied using a fluidized bed coater or an improved coating pan.

[0053] In some embodiments, the pharmaceutical solids of this disclosure comprise drug-containing granules or drug particles as described below. In some embodiments, the pharmaceutical solids are tablets comprising drug-containing granules or drug particles as described below. In some embodiments, the tablets are minitablets comprising drug-containing granules or drug particles as described below. In some embodiments, the tablets or minitablets are not prepared by wet granulation or direct compression. In some embodiments, the solids or minitablets are prepared by roller compression of drug particles or drug-containing granules as described below.

[0054] Drug-containing granules of this disclosure In some embodiments, the pharmaceutical solids disclosed herein include drug-containing granules or drug particles. In some embodiments, the drug-containing granules include ibutamorene or a pharmaceutically acceptable salt thereof. In some embodiments, the drug-containing granules include ibutamorene or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients disclosed herein. In some embodiments, the drug-containing granules include ibutamorene or a pharmaceutically acceptable salt thereof and a binder, filler, disintegrant, and / or lubricant. In some embodiments, the ibutamorene salt is ibutamorene mesylate. In some embodiments, the drug-containing granules are roller-compressed drug-containing granules.

[0055] In some embodiments, the drug-containing granules of this disclosure have a bulk density of less than 1 g / cc, less than 0.9 g / cc, less than 0.8 g / cc, less than 0.7 g / cc, less than 0.6 g / cc, or less than 0.5 g / cc, encompassing all values ​​and partial ranges between them. In some embodiments, the drug-containing granules have a bulk density of less than 0.6 g / cc. In some embodiments, the drug-containing granules have a bulk density of less than 0.5 g / cc.

[0056] In some embodiments, the drug-containing granules of the present disclosure have a tap density of less than 1 g / cc, less than 0.90 g / cc, less than 0.8 g / cc, less than 0.75 g / cc, less than 0.7 g / cc, less than 0.65 g / cc, or less than 0.6 g / cc, encompassing all values ​​and partial ranges between them. In some embodiments, the drug-containing granules have a tap density of less than 0.75 g / cc. In some embodiments, the drug-containing granules have a tap density of less than 0.6 g / cc.

[0057] In some embodiments, the drug-containing granules of the Disclosure have a bulk density of less than about 0.6 g / cc and a tap density of less than about 0.75 g / cc. In some embodiments, the drug-containing granules of the Disclosure have a bulk density of less than about 0.5 g / cc and a tap density of less than about 0.6 g / cc.

[0058] The flow properties of drug-containing granules can be estimated by calculating the Hauser ratio, which, as used herein, is the ratio of tap density to bulk density. In some embodiments, roller-compressed drug-containing granules have a Hausner ratio of about 1.0 to about 1.4. In some embodiments, roller-compressed drug-containing granules have a Hausner ratio of about 1.15 to about 1.4. In some embodiments, roller-compressed drug-containing granules have a Hausner ratio of about 1.0 to about 1.25. In some embodiments, roller-compressed drug-containing granules have a Hausner ratio of about 1.0 to about 1.2. In some embodiments, roller-compressed drug-containing granules have a Hausner ratio of about 1.15 to about 1.25 when the drug load, for example, ibutamorene mesylate, is about 60% to about 90% by weight of the pharmaceutical solids. In some embodiments, the roller-compressed drug-containing granules have a Hausner ratio of approximately 1.20 when, for example, the drug load of ibutamorene mesylate is approximately 90% by weight of the pharmaceutical solids. The correlation between fluidity and the Hausner ratio is shown in Table 3 below.

[0059] The compressibility of drug-containing granules can be estimated by calculating the curl index using the following formula:

number

[0060] In some embodiments, the roller-compressed drug-containing granules have a curl index of about 10% to about 30%. In some embodiments, the roller-compressed drug-containing granules have a curl index of about 15% to about 30%. In some embodiments, the roller-compressed drug-containing granules have a curl index of about 10% to about 20%. In some embodiments, the roller-compressed drug-containing granules have a curl index of about 15% to about 20%. In some embodiments, the roller-compressed drug-containing granules have a curl index of about 15% to about 20% when the drug load of ibutamoren mesylate is about 70% to about 90% by weight of the pharmaceutical solid. In some embodiments, the roller-compressed drug-containing granules have a curl index of about 16% when the drug load of ibutamoren mesylate is about 90% by weight of the pharmaceutical solid. The correlation between compressibility and curl index is shown in Table 3 below.

[0061] Without being bound by any particular theory, it was surprisingly and unexpectedly discovered that roller-compressed blends of drug-loaded granules containing 10% to 90% ibutamorene mesylate possessed unique and beneficial properties compared to pre-compressed blends (e.g., the first blend in Figure 1). In particular, roller-compressed blends (e.g., the RC-ground blend in Figure 1) were found to produce drug granules with lower density and larger particle size, with density decreasing and particle size increasing as the drug load level within the granules increased (Tables 2A and 2B).

[0062] This result is contrary to expectations. For example, as the drug load increases, the density of the granules typically decreases, and the particle size of the granules becomes smaller. When the particle size becomes smaller (there is a larger amount of fine particles), it becomes difficult to compress the drug granules, i.e., to compress them into tablets or minitablets, and as a result, desirable pharmaceutical tablet properties such as hardness and abrasion resistance required for the storage and transportation of tablets in the pharmaceutical industry cannot be obtained.

[0063] Unlike conventional technologies, the granules of the present invention enable high drug loading with a large particle size, and are therefore easily compressed into tablets with desirable hardness and abrasion resistance. In this invention, it was found that all drug-loaded granules processed by roller compression showed an increased proportion of larger particles compared to pre-compressed blends (Tables 2A and 2B). Unexpectedly, the resulting shift in particle size distribution (PSD) to larger particles was most pronounced in granules loaded with approximately 70% to 90% ibutamorene mesylate, with a D50 exceeding 400 μm compared to approximately 170 μm for pre-compressed drug-containing granules with these drug loadings.

[0064] In particular, the combination of unexpected density increases at high drug loading levels and the transition to larger PSDs improves the fluidity of the material, making it possible to compress it into small tablets and mini-tablets containing ≥50% or ≥70% ibutamorene mesylate, which was previously difficult to prepare with appropriate properties. In fact, for tablets with high drug loading and that are easily compressible, one embodiment of the present invention is a combination of a pharmaceutical solid (such as a mini-tablet) containing at least 10% by weight, at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of ibutamorene mesylate, and a pharmaceutical solid such as a tablet, where the weight of the tablet is less than approximately 30 mg, 20 mg, 15 mg, or 12 mg.

[0065] In some embodiments, the pharmaceutical solid comprises drug-containing granules having a D50 greater than approximately 175 μm. In some embodiments, if ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount exceeding 50% by weight of the solid, the drug-containing granules have a D50 greater than approximately 175 μm.

[0066] In some embodiments, the pharmaceutical solid comprises drug-containing granules having a D50 greater than approximately 400 μm. In some embodiments, if ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount exceeding 70% by weight of the solid, the drug-containing granules have a D50 greater than approximately 400 μm. In some embodiments, if ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount ranging from approximately 70% to approximately 90% by weight of the solid, the drug-containing granules have a D50 greater than approximately 400 μm.

[0067] In some embodiments, the drug-containing granules are compressible drug-containing granules. In some embodiments, the compressible drug-containing granules have a D50 that is at least about 1.5 times greater than that of uncompressible drug-containing granules having the same composition. In some embodiments, the compressible drug-containing granules have a D50 that is at least about 2 times greater than that of uncompressible drug-containing granules having the same composition. In some embodiments, the compressible drug-containing granules have a D50 that is at least about 2.5 times greater than that of uncompressible drug-containing granules having the same composition.

[0068] In some embodiments, the drug-containing granules contain ibutamorene or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is a mesylate.

[0069] In some embodiments, the drug-containing granules further comprise one or more binders, fillers, and / or lubricants.

[0070] In some embodiments, the drug-containing granules include a binder in an amount ranging from about 2% w / w to about 60% w / w, a bulking agent in an amount ranging from about 1% w / w to about 40% w / w, a disintegrant in an amount ranging from about 1% w / w to about 5% w / w, and a lubricant in an amount ranging from about 0.5% w / w to about 2% w / w.

[0071] In some embodiments, the drug-containing granules include a binder in an amount ranging from about 2% w / w to about 30% w / w, a bulking agent in an amount ranging from about 1% w / w to about 20% w / w, a disintegrant in an amount ranging from about 1% w / w to about 2% w / w, and a lubricant in an amount ranging from about 0.5% w / w to about 1.5% w / w.

[0072] Suitable binder materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums (e.g., sodium acacia alginate, polyvinylpyrrolidone), cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, etc.), and bee gum, as well as combinations thereof. Examples of polyvinylpyrrolidone include povidone, copovidone, and crospovidone.

[0073] Expanders, also called diluents, include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, urea, sodium chloride, sugars, or combinations thereof. Any suitable sugar may be used in the compositions of the present invention. As used herein, “sugars” as used in the present invention includes sugar alcohols, monosaccharides, disaccharides, and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, lactitol, pentitol, and hexitol. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldose, and ketose. Exemplary disaccharides include, but are not limited to, sucrose, isomalt, lactose, trehalose, and maltose. Exemplary oligosaccharides include, but are not limited to, fructooligosaccharides, inulin, galactooligosaccharides, and mannanoligosaccharides. In some embodiments, the sugar is sorbitol, mannitol, or xylitol. In some embodiments, the sugar is mannitol.

[0074] The disintegrants include, but are not limited to, starch, clay, cellulose, algin, gum, or crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone). Other non-limiting examples of suitable disintegrants include lactose, white sugar, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. In some embodiments, one or more disintegrants are lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modified starch, croscarmellose sodium, crospovidone, sodium glycolate starch, or combinations and mixtures thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0075] Suitable lubricants for the pharmaceutical solids of this disclosure include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, and the like. In some embodiments, the lubricant includes stearic acid and / or stearate, for example, magnesium stearate. In some embodiments, the pharmaceutical solid (e.g., mini-tablets) contains about 0.1% to 5%, for example, about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5%, based on the total weight of the pharmaceutical solid, including all values ​​and partial ranges in between.

[0076] In some embodiments, the drug-containing granules include a binder, a bulking agent, a disintegrant, and a lubricant. In some embodiments, the binder is pregelatinized starch, the bulking agent is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0077] In some embodiments, the drug-containing granules are processed by roller compression, for example, according to the manufacturing parameters disclosed herein.

[0078] Pharmaceutical composition Mini-tablets, beads, and sprinkle formulations prepared according to the roller compression manufacturing method described herein offer significant advantages, including administration flexibility and patient adherence, when treating pediatric patient populations with GH deficiency. For example, compressed tablets containing about 10% to about 90% by weight of ibutamorene mesylate, which can be prepared by the roller compression method disclosed herein, are small in size, allowing for the provision of compositions with different doses of ibutamorene (e.g., capsules, sachets, etc.), thereby improving administration flexibility and adherence in children with a wide range of body weights, ultimately leading to more beneficial outcomes in the treatment of pediatric patient populations.

[0079] Accordingly, in some embodiments, the pharmaceutical compositions disclosed herein include a plurality of minitablets, for example, 1 to 30 minitablets, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 minitablets, and include all partial ranges in between. In some embodiments, the minitablets are contained in capsules or sachets for oral administration. In some embodiments, the minitablets are contained in capsules for oral administration. In some embodiments, the capsules are hard gelatin or hydroxypropyl methylcellulose (HPMC) capsules. In some embodiments, the capsule contains 2 to 30 minitablets, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 minitablets, including all partial ranges in between. In some embodiments, the capsule contains 3 to 12 minitablets, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 minitablets, including all partial ranges in between. In some embodiments, the capsule contains 3, 4, or 12 minitablets. In some embodiments, the capsule contains 3 minitablets. In some embodiments, the capsule contains 4 minitablets. In some embodiments, the capsule contains 5 mini-tablets. In some embodiments, the capsule contains 6 mini-tablets. In some embodiments, the capsule contains 7 mini-tablets. In some embodiments, the capsule contains 8 mini-tablets. In some embodiments, the capsule contains 9 mini-tablets. In some embodiments, the capsule contains 10 mini-tablets. In some embodiments, the capsule contains 11 mini-tablets. In some embodiments, the capsule contains 12 mini-tablets.

[0080] In some embodiments, the capsules disclosed herein contain 3 to 12 minitablets, each containing 10% by weight of ibutamorene mesylate. In some embodiments, the capsules disclosed herein contain 3 to 12 minitablets, each containing 20% ​​by weight of ibutamorene mesylate. In some embodiments, the capsules disclosed herein contain 3 to 12 minitablets, each containing 30% by weight of ibutamorene mesylate. In some embodiments, the capsules disclosed herein contain 3 to 12 minitablets, each containing 50% by weight of ibutamorene mesylate. In some embodiments, the capsules disclosed herein contain 3 to 12 minitablets, each containing 70% by weight of ibutamorene mesylate. In some embodiments, the capsules disclosed herein contain 3 to 12 minitablets, each containing 90% by weight of ibutamorene mesylate.

[0081] The pharmaceutical compositions disclosed herein may contain multiple sprinkles. For example, 100 or more sprinkles may be incorporated into the pharmaceutical composition. In another embodiment, the amount of sprinkles in the pharmaceutical composition may be in the range of 10 to 50 sprinkles, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50 sprinkles, including all partial ranges in between. In some embodiments, the sprinkles are contained in capsules or sachets for oral administration. In some embodiments, when the sprinkles are contained in capsules, the capsule is opened and the sprinkles are added to soft food for oral administration. In some embodiments, the capsules are hard gelatin or hydroxypropyl methylcellulose (HPMC) capsules. In some embodiments, the capsule contains 10 to 50 sprinkles, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50 sprinkles, including all partial ranges in between.

[0082] In certain embodiments, the pharmaceutical compositions described herein may be provided in the form of a kit. In certain embodiments, the kit may comprise one or more pharmaceutical solids and / or one or more pharmaceutical compositions. In certain embodiments, the kit may comprise one or more tablets enclosed in capsules.

[0083] In another embodiment, the pharmaceutical solid and / or one or more pharmaceutical compositions contain ibutamorene mesylate in doses ranging from about 4 mg to about 6 mg, about 6 mg to about 8 mg, and / or about 9 mg to about 11 mg. In a particular embodiment, the kit contains a capsule containing one or more tablets having doses of ibutamorene mesylate ranging from about 4 mg to about 6 mg, about 6 mg to about 8 mg, and / or about 9 mg to about 11 mg. In another embodiment, the kit contains at least one capsule containing 1 to 6 tablets having doses of ibutamorene mesylate ranging from about 4 mg to about 6 mg, and / or at least one capsule containing 2 to 12 tablets having doses of ibutamorene mesylate ranging from about 6 mg to about 8 mg, and / or at least one capsule containing 2 to 10 tablets having doses of ibutamorene mesylate ranging from about 9 mg to about 11 mg.

[0084] Treatment method Methods for treating growth hormone (GH) deficiency in children are described in U.S. Patents 10,898,472, 10,105,352, and 9,763,919, which are incorporated herein by reference in their entirety. However, in the pediatric patient population requiring treatment, challenges remain regarding dosage flexibility and patient adherence, in addition to the need for improved efficacy.

[0085] As described above, pharmaceutical compositions including the disclosed pharmaceutical compositions (e.g., mini-tablets, beads, and sprinkle formulations) prepared according to the roller compression manufacturing method described herein offer significant advantages in treating growth hormone deficiency in pediatric patients.

[0086] Accordingly, in some embodiments, the present disclosure provides a method for treating growth hormone deficiency, the method comprising administering one or more pharmaceutical solids or pharmaceutical compositions disclosed herein to a subject in need thereof.

[0087] In some embodiments, the subject is a human subject. In some embodiments, the subject is a human subject aged 0 to 20 years, for example, 1 month old, 2 months old, 4 months old, 6 months old, 8 months old, 10 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, 18 years old, 19 years old, or 20 years old. In some embodiments, the subject is a human subject aged 2 to 20 years. In some embodiments, the subject is a human subject aged 3 to 13 years. In some embodiments, the human subject is an infant, i.e., a child aged 0 to 1 year.

[0088] In some embodiments, one or more solid pharmaceutical forms or compositions are administered orally once daily (qd).

[0089] In some embodiments, the present disclosure provides a method for treating growth hormone deficiency (GHD) in children, the method comprising administering a therapeutically effective amount of one or more pharmaceutical forms or pharmaceutical compositions disclosed herein to a child known to have short stature and sufficient GH secretion capacity.

[0090] In some embodiments, the child is identified as a child with severe GH deficiency, who is unable to increase peak GH to >5 μg / L and / or has a baseline IGF-I of <30 μg / L.

[0091] In some embodiments, the present disclosure provides a method for treating growth hormone deficiency (GHD) in children, the method comprising administering a therapeutically effective amount of one or more solid drug forms, such as minitablets, or a pharmaceutical composition, such as capsules, to a child known to have short stature and comparable growth potential to rhGH, provided that the child has comparable growth potential to rhGH if: (i) peak serum GH ≥ 5 μg / L in response to a single oral administration of ibutamoren mesylate, and (ii) baseline serum IGF-I > 30 ng / mL.

[0092] In some embodiments, children are known to have growth retardation. In some embodiments, children are known to have comparable growth potential to recombinant growth hormone (rhGH).

[0093] In some embodiments, the child is pre-pubescent. In some embodiments, the child is around puberty.

[0094] In some embodiments, treatment is continued for more than six months. For example, treatment by the disclosed method may be maintained for at least seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty, twenty-one, twenty-two, twenty-three, or twenty-four months. Further treatment may include at least two and a half years, three, three and a half years, four, four and a half years, four and a half years, or until growth potential ceases.

[0095] In one embodiment of the present invention, the method comprises administering one or more pharmaceutical solids disclosed herein, or pharmaceutical compositions described herein, to a subject requiring such a substance.

[0096] As described above, the pharmaceutical solids of the present invention provide desirable tablet and pharmaceutical dosage form characteristics. The pharmaceutical granules of the present invention are compressible, i.e., can be compressed into tablets or minitablets, have desirable pharmaceutical tablet characteristics, and have a high drug load of ibutamorene mesylate. In fact, in the case of tablets with a high drug load and that are easily compressible, one embodiment of the present invention also includes a method of administering a pharmaceutical solid (such as a minitablet) containing at least 10% by weight, at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of ibutamorene mesylate, and the weight of the pharmaceutical solid, such as a tablet, is less than about 30 mg, 20 mg, 15 mg, or 12 mg.

[0097] The combination of a high drug load and small tablet size allows for both medication adherence from pediatric patient populations and flexibility in administering ibutamorene mesylate to pediatric patient populations that may have widely varying body weights. Therefore, in one embodiment, pharmaceutical dosage forms such as solid preparations and tablets (such as mini-tablets) can have different doses that can be mixed and adjusted for administration to pediatric patients of any weight, such as the weight of a 2-year-old or 18-year-old child. In one embodiment, these methods may include dosage forms that can contain different doses in different tablets or mini-tablets. In another embodiment, the different doses can be placed in different capsules, which may contain tablets or mini-tablets of the same or different doses.

[0098] In certain embodiments, each pharmaceutical solid or tablet contains about 1 mg to about 15 mg of ibutamorene mesylate, or about 3 mg to about 15 mg of ibutamorene mesylate, or about 4 mg to about 6 mg of ibutamorene mesylate, or about 6 mg to about 8 mg of ibutamorene mesylate, or about 9 mg to about 11 mg of ibutamorene mesylate. In certain embodiments, each pharmaceutical solid or tablet contains about 1.0 mg, 1.5 mg, 2.0 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 2.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, or 15 mg of ibutamorene mesylate.

[0099] In another embodiment, a subject is administered multiple solid drug forms or tablets. In another specific embodiment, multiple solid drug forms or tablets can be administered freely, such as by mixing them with food or by administering them directly to the subject without food. In another embodiment, multiple solid drug forms or tablets may be administered in a dosage form in which the solid drug forms or tablets are encapsulated. In a particular embodiment, the dosage form may be a capsule. In a particular embodiment, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen solid drug forms or tablets are incorporated into a capsule for administration to the subject.

[0100] In another embodiment, multiple solid drug forms or tablets may be administered based on the drug load of the solid drug forms or tablets and the subject's body weight, for example, as shown in Table 6.

[0101] In certain embodiments, the solid drug form or tablet may be administered to the subject once, twice, three, four, five, or six times a day.

[0102] In certain embodiments, the solid drug form or tablet is administered to the subject once daily. In other embodiments, the total daily dose of ibutamorene mesylate to the subject is in the range of approximately 8 mg to approximately 120 mg, approximately 10 mg to approximately 100 mg, approximately 20 mg to approximately 75 mg, approximately 30 mg to approximately 60 mg, and approximately 40 mg to approximately 50 mg.

[0103] In certain embodiments, the therapeutic dose administered to the subject is in the range of approximately 0.1 mg / kg of body weight / day to approximately 4.0 mg / kg of body weight / day, or approximately 0.6 mg / kg of body weight / day to approximately 3.5 mg / kg of body weight / day. In other embodiments, the therapeutic dose is in the range of approximately 0.8 mg / kg / day to approximately 3.2 mg / kg / day of ibutamoren mesylate, or approximately 0.8 mg / kg / day, approximately 0.9 mg / kg / day, approximately 1.0 mg / kg / day, approximately 1.1 mg / kg / day, approximately 1.2 mg / kg / day, approximately 1.3 mg / kg / day, approximately 1.4 mg / kg / day, approximately 1.5 mg / kg / day, approximately 1.6 mg / kg / day, approximately 1.7 mg / kg / day, approximately 1.8 mg This corresponds to g / kg / day, approximately 1.9 mg / kg / day, approximately 2.0 mg / kg / day, approximately 2.1 mg / kg / day, approximately 2.2 mg / kg / day, approximately 2.3 mg / kg / day, approximately 2.4 mg / kg / day, approximately 2.5 mg / kg / day, 2.6 mg / kg / day, approximately 2.7 mg / kg / day, approximately 2.8 mg / kg / day, approximately 2.9 mg / kg / day, approximately 3.0 mg / kg / day, approximately 3.1 mg / kg / day, or approximately 3.2 mg / kg / day.

[0104] In some embodiments, the target population includes individuals taking approximately 0.8 mg / kg / day to approximately 3.2 mg / kg / day, for example, approximately 0.8 mg / kg / day, approximately 0.9 mg / kg / day, approximately 1.0 mg / kg / day, approximately 1.1 mg / kg / day, approximately 1.2 mg / kg / day, approximately 1.3 mg / kg / day, approximately 1.4 mg / kg / day, approximately 1.5 mg / kg / day, approximately 1.6 mg / kg / day, approximately 1.7 mg / kg / day, approximately 1.8 mg / kg / day, approximately 1.9 mg / kg / day, and approximately 2. Ibutamoren mesylate is administered at doses of 0 mg / kg / day, approximately 2.1 mg / kg / day, approximately 2.2 mg / kg / day, approximately 2.3 mg / kg / day, approximately 2.4 mg / kg / day, approximately 2.5 mg / kg / day, 2.6 mg / kg / day, approximately 2.7 mg / kg / day, approximately 2.8 mg / kg / day, approximately 2.9 mg / kg / day, approximately 3.0 mg / kg / day, approximately 3.1 mg / kg / day, or approximately 3.2 mg / kg / day, including all values ​​and partial ranges in between. In some embodiments, subjects are administered ibutamoren mesylate at doses of approximately 0.8 mg / kg / day, approximately 1.6 mg / kg / day, approximately 2.4 mg / kg / day, or 3.2 mg / kg / day. In some embodiments, subjects are administered ibutamoren mesylate at doses of approximately 0.8 mg / kg / day. In some embodiments, subjects are administered approximately 1.6 mg / kg / day of ibutamorene mesylate. In some embodiments, subjects are administered approximately 3.2 mg / kg / day of ibutamorene mesylate.

[0105] In some embodiments, subjects are administered ibutamoren mesylate at doses ranging from approximately 0.1 mg / kg / day to approximately 1.5 mg / kg / day, for example, approximately 0.1 mg / kg / day, approximately 0.2 mg / kg / day, approximately 0.3 mg / kg / day, approximately 0.4 mg / kg / day, approximately 0.5 mg / kg / day, approximately 0.6 mg / kg / day, approximately 0.7 mg / kg / day, approximately 0.8 mg / kg / day, approximately 0.9 mg / kg / day, approximately 1.0 mg / kg / day, approximately 1.1 mg / kg / day, approximately 1.2 mg / kg / day, approximately 1.3 mg / kg / day, approximately 1.4 mg / kg / day, or approximately 1.5 mg / kg / day, including all values ​​and partial ranges in between. In some embodiments, subjects are administered ibutamoren mesylate at doses ranging from approximately 0.6 mg / kg / day to approximately 1.0 mg / kg / day. In some embodiments, subjects are administered approximately 0.8 mg / kg / day of ibutamorene mesylate.

[0106] In some embodiments, subjects are administered one to two capsules per day, each containing up to 12 mini-tablets, based on their body weight. In some embodiments, subjects are administered one to two capsules per day, each containing 2 to 12 mini-tablets, based on their body weight. In some embodiments, subjects are administered one to two capsules per day, each containing up to 10 mini-tablets, based on their body weight. In some embodiments, subjects are administered one to two capsules per day, each containing 2 to 10 mini-tablets, based on their body weight.

[0107] In some embodiments, a dose of 0.8 mg / kg / day of ibutamorene mesylate is provided by administering 2 to 12 minitablets to the subject daily, each minitablet being a 50% drug-loaded minitablet containing approximately 4.7 mg of ibutamorene mesylate. In some embodiments, the dose is administered by one or two capsules, each capsule containing two, three, or six minitablets.

[0108] In some embodiments, a dose of 0.8 mg / kg / day of ibutamorene mesylate is provided by administering up to two capsules per day containing two, three, or six minitablets, each minitablet being a 50% drug-loading minitablet containing approximately 4.7 mg of ibutamorene mesylate.

[0109] In some embodiments, a dose of ibutamorene mesylate of 1.6 mg / kg / day is provided by administering 3 to 16 minitablets to the subject daily, each minitablet being a 70% drug-loaded minitablet containing approximately 7.11 mg of ibutamorene mesylate. In some embodiments, the dose is administered by one or two capsules, each capsule containing three, four, or twelve minitablets.

[0110] In some embodiments, a dose of 1.6 mg / kg / day of ibutamorene mesylate is provided by administering up to two capsules per day containing three, four, or twelve minitablets, each minitablet being a 70% drug-loading minitablet containing approximately 7.11 mg of ibutamorene mesylate.

[0111] In some embodiments, a dose of 3.2 mg / kg / day of ibutamorene mesylate is provided by administering 3 to 20 minitablets to the subject daily, each minitablet being an 85% drug-loading minitablet containing approximately 10.36 mg of ibutamorene mesylate. In some embodiments, the dose is administered by one or two capsules, each capsule containing three, four, or ten minitablets.

[0112] In some embodiments, a dose of ibutamorene mesylate of 3.2 mg / kg / day is provided by administering up to two capsules per day containing three, four, or ten minitablets, each minitablet being an 85% drug-loading minitablet containing approximately 10.36 mg of ibutamorene mesylate.

[0113] In some embodiments, the subject to be treated is untreated (never received growth hormone treatment). In some embodiments, the subject or child to be treated may have previously received discontinued GH treatment, provided that they meet the criteria for sufficient GH secretion capacity as confirmed above.

[0114] In some embodiments, the Disclosure provides a method for treating a disease or condition associated with an abnormal decrease in growth hormone (GH) secretion in a subject having sufficient growth hormone (GH) secretion capacity, the method comprising administering one or more pharmaceutical solids or pharmaceutical compositions disclosed herein to the subject.

[0115] In some embodiments, treatment of a disease or condition includes increasing endogenous GH secretion in the subject.

[0116] In some embodiments, the disease or condition is Turner syndrome, chronic kidney disease in children (PCKD), Prader-Willi syndrome (PWS), lipodystrophy (e.g., HIV lipodystrophy), muscular atrophy, small gestational age (SGA), idiopathic short stature (ISS), short stature homeobox-containing gene (SHOX) deficiency, Noonan syndrome, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

[0117] In some embodiments, the muscle atrophy disorder is sarcopenia, cachexia, hypothalamic amenorrhea, or relative energy deficit (RED-S) syndrome in sports.

[0118] Preparation method This disclosure also provides methods for preparing the pharmaceutical solids and compositions thereof disclosed herein.

[0119] In some embodiments, this disclosure provides compressible pharmaceutical tablets prepared by: (a) A mixture of ibutamorene or a pharmaceutically acceptable salt thereof is blended with the first part of a binder, filler, disintegrant, and lubricant. (b) Using a roller compressor, compress the blended mixture from step (a) thereby forming a compressed material. (c) The compressed material from step (b) is sieved through one or more screens to produce drug-containing granules. (d) Blend the drug-containing granules from step (c) with the second portion of the disintegrant, lubricant, and binder to obtain the final blend. (e) compress the final blend from step (d) into a compressible tablet, and (f) Optionally, the compressible tablets are coated with the coatings described herein (e.g., Eudragit® E PO).

[0120] In some embodiments, the ibutamorene salt is ibutamorene mesylate.

[0121] Binders, fillers, disintegrants, and lubricants may be any of the options described herein in any disclosed amount or range. In some embodiments, the binder is pregelatinized starch, the filler is mannitol, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

[0122] In some embodiments, the blending in step (a) is carried out for about 1 minute to about 30 minutes. In some embodiments, the blending in step (a) is carried out for about 5 minutes to about 15 minutes. In some embodiments, the blending is carried out in a blender machine, such as a V-type blender.

[0123] The roller compressor in step (b) can be operated at any suitable screw speed, roller speed, and compression pressure sufficient to prepare the compressed material of the present disclosure, as determined by those skilled in the art based on factors including, but not limited to, the size of the compressor, the type of model, and the composition of the blended mixture. In some embodiments, the roller compressor in step (b) is operated at a screw feeder speed of about 20 rpm to about 60 rpm, a roller speed of about 3 rpm to about 9 rpm, and a compression pressure of about 10 bar to about 30 bar. In some embodiments, the roller compressor in step (b) is operated at a screw feeder speed of about 40 rpm, a roller speed of about 6 rpm, and a compression pressure of about 20 bar. In some embodiments, the roller compressor includes a granulator operating at 75 rpm to 125 rpm. In some embodiments, the granulator operates at about 95 rpm.

[0124] In some embodiments, the first portion of the binder is about 25% to about 75% by weight of the total amount of binder added. In some embodiments, the first portion of the lubricant is about 25% to about 75% of the total amount of lubricant added. In some embodiments, the first portion of the binder is about 50% by weight of the total amount of binder added. In some embodiments, the first portion of the lubricant is about 50% of the total amount of lubricant added.

[0125] In some embodiments, one or more of the binder, filler, disintegrant, and lubricant from step (a) are separated by sieving before roller compression. In some embodiments, the sieve is 20 mesh or 40 mesh.

[0126] In some embodiments, the screening in step (c) includes screening the roller-compressed material through a coarse screen and / or a fine screen. In some embodiments, the screening in step (c) includes screening the roller-compressed material through a coarse screen and a fine screen. In some embodiments, the coarse screen has a size of 1.6 mm. In some embodiments, the fine screen has a size of 1.0 mm. In some embodiments, the roller compressor is fitted with a coarse screen and a fine screen.

[0127] In some embodiments, one or more of the second parts of the binder, disintegrant, and lubricant are separated through a mesh sieve before blending in step (d). In some embodiments, the sieve is a 20-mesh or 40-mesh sieve.

[0128] In some embodiments, the second portion of the disintegrant is about 50% by weight of the total amount of disintegrant added. In some embodiments, the second portion of the lubricant is about 50% of the total amount of lubricant added. [Examples]

[0129] The following examples are provided to illustrate this disclosure and should not be construed as limiting this disclosure.

[0130] Example 1. Preparation of drug-containing granules The final blends of the drug-containing granules of this disclosure, containing 10% by weight, 20% by weight, 30% by weight, 50% by weight, 70% by weight, 85% by weight, and 90% by weight of ibutamorene mesylate, were prepared by a manufacturing method including roller compression (see Figure 1) and processing parameters shown in Table 1.

[0131] [Table 2]

[0132] Example 2. Characteristics of drug-containing granules The density and particle size distribution by sieve analysis of drug-containing granules containing 10% by weight, 20% by weight, 30% by weight, 50% by weight, 70% by weight, 85% by weight, and 90% by weight of ibutamorene mesylate, prepared as described in Example 1, were compared (Tables 2A and 2B). The following tables compare the initial blend before roller compression (before RC) with the crushed blend after roller compression (see Figure 1) (hereinafter also referred to as after RC).

[0133] [Table 3]

[0134] [Table 4]

[0135] As shown in Tables 2A and 2B, the drug-containing granules produced by roller compression exhibit significant compressibility as the drug load increases. A general trend observed is that densification decreases as the drug load of ibutamorene mesylate increases, but the particle size distribution (PSD) of the blend after RC shifts to larger particle sizes compared to the blend before RC.

[0136] Table 3 shows the calculation of the Hausner ratio and Karl index, respectively, for estimating the flowability and compressibility indices of powder blends / granules. Table 4 provides guidance on the flowability properties of powder blends / granules.

[0137] [Table 5]

[0138] [Table 6]

[0139] The data above demonstrates that ibutamorene mesylate exhibits unique compressibility characteristics at low (10%) and high (90%) drug loads, resulting in roller-compressed granule / powder blends with suitable sieve analysis (particle size distribution) and density (bulk and tap) for compression. In all drug load preparations, the roller compression process resulted in an increased amount of large granules (i.e., granules held by 40, 60, and 80 mesh sieves) along with increased blend density (increased bulk density) compared to before roller compression. Without being bound by specific theories, controlling the granule size distribution and avoiding large amounts of fine particles is crucial to minimizing powder separation in a proper flow during compression. Granule density measurements before and after roller compression are supported by USP <616> Measurements were taken according to the following criteria. In all cases, densification of the blend was observed, but densification decreased as the drug load increased (90% < 85% < 70% < 50% < 30% < 20% < 10%), and the fluidity and compressibility of the blend improved as the drug load increased.

[0140] Example 3. Preparation of Compression Tablets The final blend of drug-containing granules and external excipients (binders, disintegrants, and / or lubricants), as described above and in Figure 1, was compressed into tablets using a rotary tablet press. The tablets were manufactured by pressing the blend containing drug-containing granules and external excipients in the center of the die using two punches that fit into the upper and lower parts of the die. Both punches move between two large wheels (pressure rolls), which press the punches together to form the tablet with a specific compressive force. The distance between the upper and lower punches and the compressive force determine the thickness and hardness of the tablet while keeping the tablet weight constant.

[0141] Example 4. Characteristics of Compression Tablets The properties, including hardness and abrasion resistance, of the tablets produced according to Example 3 are provided in Table 5.

[0142] [Table 7]

[0143] Each ibutamoren mesylate drug-loaded tablet was successfully compressed using a 2.5 mm round tool. All tablet batches exhibited less than 1% abrasion and a hardness ranging from 0.8 kP to 5.2 kP before coating. Data showed that tablet hardness generally increased with increasing drug load. After compression, all batches were successfully coated with a 20% weight increase.

[0144] When the compressed blend was compressed into tablets using a 2.5 mm tool (see Figure 1), it was unaffected by the ibutamorene mesylate drug loading. All tablets were prepared within the USP weight variation limit of 10% and with abrasion of 1.0% or less. In each drug loading, the hardness of the tablets was sufficient to withstand the fluidized bed coating process. In each drug loading, mini-tablet dissolution of 85% (Q=80%) or more (NLT) was achieved in 30 minutes.

[0145] Example 5. Efficacy study in children with growth hormone (GH) deficiency. Summary: This study will be conducted to determine whether the mini-tablets disclosed herein can be used for the treatment of GHD in children. The disclosed mini-tablets will be compared with rhGH injections according to the following protocol. Bone age will be determined using atlas matching of the Greulich and Pyle protocols, and subjects will be randomly assigned to receive either a mini-tablet providing one of three oral daily doses of ibutamoren mesylate, or daily injections of recombinant human growth hormone (rhGH).

[0146] This study will include treatment for up to 24 months. Participants will undergo physical examinations and blood and urine samples to assess their response to treatment.

[0147] Participants: Children aged 3 to 12 years, both male and female, who have been diagnosed with idiopathic PGHD according to standard diagnostic criteria and who have sufficient GH secretion capacity. • Has an HT-SDS ≤ -2.0 or HT-SDS ≥ 2SD, which is lower than the mean parent HT-SDS. • Based on growth over at least 6 months, the child has a baseline height growth rate of <5.5 cm / year. • Has a bone age that is ≥6 months behind chronological age. In girls, prepubescent status is indicated by Tanner stage I breast development; in boys, by testicular volume <4.0 mL.

[0148] Treatment groups and dosages (Table 6): • 0.8 mg / kg / day of ibutamoren mesylate is administered orally once daily in the form of a mini-tablet. • Administer 1.6 mg / kg / day of ibutamoren mesylate orally once daily in the form of a mini-tablet. • 3.2 mg / kg / day of ibutamoren mesylate is administered orally once daily in the form of mini-tablets. • 34 μg / kg / day of rhGH administered subcutaneously once daily (comparison with active drug)

[0149] The primary outcomes include the following: • Annual height velocity (AHV) measured with a height measuring device. Comparison of AHV and rhGH measured after taking the disclosed mini-tablets containing ibutamoren mesylate for 6 months.

[0150] Secondary outcomes may include the following: • Determining changes in bone age - X-ray measurement of the left hand and wrist using the Greulich and Pyle atlas. • Pharmacokinetic evaluation Changes in weight, BMI, and other parameters • Height Standard Deviation Score (SDS) and Height Velocity Standard Deviation Score (HV-SDS)

[0151] Conclusion: Subjects diagnosed with GHD and treated with the mini-tablets of this disclosure show improved outcomes with each dose of ibutamorene mesylate administered, as determined by AHV and other measured parameters, compared to subjects who received subcutaneous rhGH.

[0152] [Table 8]

[0153] summary Generally, high-drug-load formulations are difficult to prepare using roller compression processes. While blend properties and processability can be improved by selecting appropriate amounts of suitable excipients at low drug loads, this option is limited at high drug loads. Therefore, the physical properties of drug substances exhibiting comparable blend and tablet properties at both low and high drug loads present a challenge to be addressed by the pharmaceutical solids and manufacturing methods disclosed herein.

[0154] Built-in by reference All publications and patents referenced herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In the event of any conflict, including any definitions herein, this application shall prevail.

[0155] Equal portions While specific embodiments of the disclosure have been considered, the above specification is illustrative and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon further consideration of this specification and the following claims. The full scope of the disclosure should be determined by reference to the claims, their equivalents, the specification, and any such modifications.

Claims

1. A tablet for use in the treatment of childhood growth hormone deficiency, (a) Multiple drug-containing granules comprising ibutamorene or a pharmaceutically acceptable salt thereof, and an internal excipient, wherein the ibutamorene or a pharmaceutically acceptable salt thereof is in an amount of 50% by weight or more of the tablet, and the internal excipient comprises a binder in an amount ranging from 2% w / w to 60% w / w selected from the group consisting of corn starch, pregelatinized starch, gelatin, polyvinyl alcohol, wax, sodium acacia alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, and combinations thereof, a bulking agent in an amount ranging from 1% w / w to 40% w / w, an internal disintegrant in an amount ranging from 1% w / w to 5% w / w including croscarmellose sodium, crospovidone, sodium glycolate starch, or combinations thereof, and an internal lubricant in an amount ranging from 0.5% w / w to 2% w / w, and (b) Granular excipients Includes, The aforementioned tablet has a weight of less than 20 mg, a diameter of less than 5 mm, and The aforementioned tablet has a hardness greater than 0.7 kp and a degree of abrasion of less than 1%.

2. The tablet according to claim 1, wherein the ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 50% to 90% by weight of the tablet.

3. The tablet according to claim 1, wherein the ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 60% to 80% by weight of the tablet.

4. The tablet according to claim 1, wherein the pharmaceutically acceptable salt is ibutamoren mesylate.

5. The tablet according to claim 1, wherein the amount of the binder is in the range of 2% w / w to 30% w / w, the amount of the bulking agent is in the range of 1% w / w to 20% w / w, the amount of the granular disintegrant is in the range of 1% w / w to 5% w / w, and the amount of the granular lubricant is in the range of 0.5% w / w to 2% w / w.

6. The tablet according to claim 1, wherein the bulking agent is a sugar alcohol selected from the group consisting of xylitol, mannitol, sorbitol, erythritol, lactitol, pentitol, and hexitol.

7. The tablet according to claim 6, wherein the granular lubricant is magnesium stearate, calcium stearate, colloidal silica, talc, or a combination thereof.

8. The tablet according to claim 1, wherein the external excipient comprises an external disintegrant and an external lubricant.

9. The tablet according to claim 8, wherein the amount of the extragranular disintegrant is in the range of 1% w / w to 5% w / w, and the amount of the extragranular lubricant is in the range of 0.5% w / w to 5% w / w.

10. The tablet according to claim 8, wherein the external lubricant is magnesium stearate, calcium stearate, colloidal silica, talc, or a combination thereof, and the external disintegrant is carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, sodium glycolate starch, low-substituted hydroxypropylcellulose, or a combination thereof.

11. The tablet according to claim 1, wherein the drug-containing granules have a bulk density of less than 0.6 g / cc and / or a tap density of less than 0.78 g / cc.

12. The tablet according to claim 1, wherein the drug-containing granules have a D50 of more than 175 μm.

13. The tablet according to claim 1, wherein the drug-containing granules have a D50 of more than 400 μm.

14. The tablet according to claim 1, wherein the diameter of the tablet is less than 4 mm or less than 3 mm.

15. The tablet according to claim 1, wherein the diameter of the tablet is less than 4 mm.

16. The tablet according to claim 1, having a hardness of 1.5 Kp to 6 Kp when using a tablet tool size of 2.5 mm.

17. The tablet according to claim 1, wherein the tablet is a coated tablet.

18. The tablet according to claim 17, wherein the coated tablet comprises one or more coating layers.

19. The tablet according to claim 18, wherein the one or more coating layers include an N,N-dimethylaminoethyl methacrylate / methacrylate / butyl methacrylate copolymer or a polyvinyl alcohol (PVA) based coating that does not contain polyethylene glycol.

20. The tablet according to claim 18, wherein the one or more coating layers give a weight increase of 5% to 25% by weight based on the total weight of the tablet.

21. The tablet according to claim 18, wherein the one or more coating layers give a weight increase of 8% to 20% by weight based on the total weight of the tablet.

22. A pharmaceutical composition comprising a plurality of tablets as described in claim 1.

23. The pharmaceutical composition according to claim 22, wherein the composition is in the form of a capsule containing 2 to 12 tablets.

24. The pharmaceutical composition according to claim 23, wherein the composition is in the form of a capsule containing 3, 4, or 12 of the tablets.

25. The pharmaceutical composition according to claim 23, wherein the capsule is a hard gelatin or hydroxypropyl methylcellulose (HPMC) capsule.

26. The pharmaceutical composition according to claim 22, wherein the ibutamorene or a pharmaceutically acceptable salt thereof is present in an amount of 50% to 90% by weight of each tablet.

27. ​​A tablet according to any one of claims 1 to 21, for use in the treatment of growth hormone deficiency in pediatric patients.

28. A pharmaceutical composition according to any one of claims 22 to 26, for use in the treatment of growth hormone deficiency in pediatric patients.

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